DESCRIPTION (provided by candidate): Nonalcoholic fatty liver disease (NAFLD) is a group of diseases characterized by hepatic steatosis without significant alcohol use, often associated with hyperlipidemia, obesity and insulin resistance. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD, with steatosis and added necroinflammation and fibrosis. NASH is common and may progress to cirrhosis. The pathogenesis of NAFLD is unknown but may incorporate a polygenic susceptibility with a phenotype strongly influenced by environmental factors. Disorders of lipid homeostasis underlie all forms of hepatic steatosis. Fat accumulation as triglyceride (TG) in the hepatocyte is the critical first step in the development of NAFLD. The central hypothesis of this proposal is that the pathogenesis of NAFLD is based upon increased flux of TG precursors (fatty acids, FA) with increased synthesis or decreased mobilization of TG in the hepatocyte, leading to fat accumulation. We postulate that NAFLD evolves to NASH when genetic abnormalities of fatty acid flux and environmental factors converge. Triglyceride accumulation may relate to increased peripheral FA mobilization, regulated in part by peroxisome proliferator-activated receptor gamma (PPARgamma). Alternatively, FA within the hepatocyte may be misdirected from oxidative pathways to TG synthesis: genomic variants in PPARalpha are likely candidates. Impaired lipidation and hepatocyte VLDL secretion would also potentiate steatosis and variants in Microsomal Triglyceride Transfer Protein (MTP) and apo-B render these as further prime candidate genes. Clinical and tissue databases at UCSF will be utilized and further characterized. The specific aims are (1) To perform mutation analysis on key genes of lipid metabolism, PPARalpha, PPARgamma, MTP and apo-B, for known and novel mutations in patients with NASH. We aim to extend our preliminary data showing increased prevalence of genomic variants of PPARalpha in patients with NASH, supporting our postulate that these are important in disease progression (2) To genotype polymorphisms detected, permitting screening of case control sample populations (3) To assess the contribution to NASH of genomic variants uncovered, in kindred identified with NASH, using cosegregation analysis (4) To determine the biochemical effects of mutants using in-vitro transfection studies. These projects will increase our understanding of NASH and with mentoring and coursework will foster the candidate's development as an independent researcher.